We plan a multidisciplinary study of certain biochemical, physiological and pathologic sequences involved in acute lung injury and repair. Complementary clinical and laboratory investigations of acute lung injury will: elucidate the initial causes and sequences of pulmonary vascular injury during severe adult respiratory distress syndrome (ARDS) by using hemodynamic and digital subtraction angiographic studies as well as quantitative light microscopy and ultrastructural analysis, investigate agents controlling the pulmonary endothelial cell cytoskeleton focusing on injured lung cell biology, study the interaction of the coagulation system with the acutely injured lung, and learn how eicosanoid metabolities particularly the leokotrienes mediate lung injury and cardiac depression. We plan to develop new diagnostic techniques to measure the changes of pulmonary artery impedance during ARDS as well as image intrapulmonary thrombosis. We shall examine the basic mechanisms and pathogenesis of pulmonary thromboembolism, vasospasm and microvascular edema in acute respiratory failure of diverse etiology. We hope to test our newly acquired knowledge of the mechanisms of ARDS by pilot therapy with drugs that are thrombolytic, antifibrotic, and inhibitors of thromboxane synthetase. Since they may be central to several lung injury mechanisms, we will investigate eicosanoid and specifically leukotriene metabolism using radioimmunoassay and high pressure liquid chromatography.